A single dose of nevirapine (SD NVP) given to an HIV infected pregnant woman followed by a single dose to her infant has been shown to be an effective way of reducing the risk of mother-to-child transmission (MTCT) of HIV. The purpose of this study was to compare the effectiveness of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP for prevention of MTCT.

Phase II, Parallel, Randomized, Clinical Trials Comparing the Responses to Initiation of NNRTI-Based Versus PI-Based Antiretroviral Therapy in HIV Infected Infants Who Have and Have Not Previously Received Single Dose Nevirapine for Prevention of Mother-to-Child HIV Transmission

Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment [ Time Frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ] [ Designated as safety issue: No ]

Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR permanent discontinuation of the randomized NNRTI or PI component of study treatment at or prior to 24 weeks of treatment for any reason including death. Results report percent of participants reaching a treatment failure endpoint by week 24 calculated using the Kaplan-Meier method.

Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR permanent discontinuation of the randomized NNRTI or PI component of study treatment for any reason including death.

Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method.

Virologic failure is defined as the earlier of a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR death.

Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment [ Time Frame: On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ] [ Designated as safety issue: Yes ]

Safety events include lab abnormalities, signs or symptoms of grade 3 or higher. Events were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, Version 1.0. Events defined as new if first occurrence was after initiation of study treatment or if severity increased from entry and while on the NNRTI or PI component of study treatment.

Change was calculated as CD4 percent at week 48 minus entry CD4 percent (last CD4 percent before randomization date). Only subjects who reached 48 weeks of follow-up before DSMB decisions to unblind each Cohort were included in summary.

16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg

16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg

age >=6 months to < 36 months (decreased to 2 months in protocol version 4.0)

HIV infected

Viral load greater than 5,000 copies/ml within 60 days of study entry

Treatment naive except for antiretrovirals (ARV) used to prevent MTCT (infant ARV use for <=1 week postpartum for prevention of MTCT allowed)

Eligible for treatment according to WHO pediatric algorithm (updated in protocol version 1.0, Letter of amendment (LOA)#1) and protocol version 2.0, LOA#3). Subjects with active opportunistic infections were not eligible for study participation until they had been treated and were clinically stable

Parent or legal guardian willing to provide signed informed consent

Inclusion Criteria for Cohort I:

Documentation of maternal or infant NVP exposure or a highly reliable verbal report. (Updated in protocol version 2.0, LOA#3 to require written clinic/hospital documentation of infant exposure to SD NVP)

Use of maternal ARV, including NVP, permitted during pregnancy

One or more of the following: strict formula feeding, initial infant HIV diagnosis occurring while younger than 60 days of age, or an initial AIDS-defining illness diagnosis by WHO criteria while younger than 60 days of age.

Inclusion Criteria for Cohort II:

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Use of maternal ARVs, excluding NNRTIs, permitted during pregnancy

Evidence of lack of prior NVP exposure (added in protocol version 2.0, LOA#3) by review of maternal and child medical records or health card (or other written documentation) for evidence of NVP exposure to mother or infant during pregnancy, labor, and delivery. If no written documentation showing lack of NVP use was shown in these records or if these records were not available for review, then a verbal report considered to be highly reliable by the study nurse was acceptable AND one or more of the following:

Study subject born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject

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Study subject born before the biological mother's first positive HIV test

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Site staff had another reason to believe the subject had not been exposed to NVP

Received ARVs for anything other than the prevention of intrapartum MTCT. Infants who received ARVs after the first week of life (e.g., for the prevention of MTCT of HIV through breastfeeding) were excluded

Acute serious infections requiring active treatment. Subjects could be receiving treatment for active TB if it did not include rifamycin drugs

Receiving chemotherapy for an active tumor >>

History of a cardiac conduction abnormality and underlying structural heart disease

Required certain medications

Exclusion Criteria for Cohort I:

History of or currently breastfeeding. Breastfed infants with a positive HIV test or who had experienced an AIDS-defining illness by WHO criteria at 60 days of age or younger were not excluded

Exclusion Criteria for Cohort II:

Exposure to any maternal NVP or other NNRTI prior to or during the pregnancy or while breastfeeding

Exposure of infant to NVP at any time including during the first week of life

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00307151